Abstract Lynch syndrome is an inherited cancer susceptibility syndrome caused by mutation in one of several DNA mismatch repair (MMR) genes, including MSH2, MSH6, MLH1, PMS2, and EPCAM. Women with Lynch syndrome are at high risk for endometrial (uterine) cancer, colon cancer, as well as other tumor types. While there has been significant progress in the understanding of Lynch syndrome associated colon cancer in terms of molecular pathogenesis and risk, Lynch syndrome associated endometrial cancer is less well understood. The lifetime risk of endometrial cancer in women with Lynch syndrome has been estimated near 54%, and may equal or exceed the risk of colorectal cancer. MSH2 is one of the most commonly mutated MMR genes (50- 66%) in Lynch syndrome associated endometrial cancer. In addressing provocative question #2, we will evaluate mechanisms underlying how endometrial cancer penetrance associated with loss of MSH2 is influenced by patient natural history (exposure to natural or synthetic hormones) and obesity. We have developed a novel, uterine-targeted, MSH2 knockout mouse model of Lynch syndrome that closely mimics the progression to endometrial cancer observed in women. This model enables us to probe molecular mechanisms underlying how these environmental factors change the risk of endometrial cancer in women with Lynch syndrome. Obesity and exposure to estrogen are associated with increased sporadic (not inherited) endometrial cancer risk and are known to alter endometrial cell growth, growth factor signaling, as well as the immune response and inflammation. We hypothesize that in the absence of MSH2, behaviors/factors that amplify these changes in the endometrium will increase the likelihood of acquiring oncogenic mutations. Conversely, we expect that environmental factors or behaviors that decrease endometrial cell growth and normalize growth factor signaling and immune response (by lowering exposure to detrimental hormones or by maintaining a lean weight and low insulin), will reduce the overall incidence and accumulation of oncogenic mutations, and decrease the penetrance of disease in women with Lynch syndrome. We will evaluate the molecular changes that occur in the endometrium of normal mice and MSH2 knockout mice in response to hormone exposure and obesity using state-of-the-art tools for molecular profiling. We expect to identify a subset of genes that are targets for mutation in the absence of MSH2, which contribute to the development of endometrial cancer in Lynch Syndrome. We will further examine how changes in the local immune response is altered due to the loss of MSH2 and how this is impacted by hormones and obesity. These findings will be critical to developing effective prevention strategies (both behavioral and pharmaceutical), which can delay or prevent endometrial cancer in these women.